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Found 35618 matches. Displaying 11-20
Bonagura VR, Casanova JL
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Past, Present, and Future of The Journal of Clinical Immunology, the International Journal of Inborn Errors of Immunity

Muller PA, Matheis F, Schneeberger M, Kerner Z, Jove V, Mucida D
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Microbiota-modulated CART(+) enteric neurons autonomously regulate blood glucose

SCIENCE 2020 OCT 16; 370(6514):314-321
The gut microbiota affects tissue physiology, metabolism, and function of both the immune and nervous systems. We found that intrinsic enteric-associated neurons (iEANs) in mice are functionally adapted to the intestinal segment they occupy; ileal and colonic neurons are more responsive to microbial colonization than duodenal neurons. Specifically, a microbially responsive subset of viscerofugal CART(+) neurons, enriched in the ileum and colon, modulated feeding and glucose metabolism. These CART(+) neurons send axons to the prevertebral ganglia and are polysynaptically connected to the liver and pancreas. Microbiota depletion led to NLRP6- and caspase 11-dependent loss of CART(+) neurons and impaired glucose regulation. Hence, iEAN subsets appear to be capable of regulating blood glucose levels independently from the central nervous system.
Bournazos S, Gupta A, Ravetch JV
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The role of IgG Fc receptors in antibody-dependent enhancement

Antibody-dependent enhancement (ADE) has been described as a mechanism that contributes to the pathogenesis of dengue virus infection. Limited evidence also suggests that it can also occur in other viral infections. Here, the authors explore the history of the ADE phenomenon, discuss the diversity of Fc effector functions and consider its potential relevance in the context of SARS-CoV-2 infection. Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fc gamma receptor (Fc gamma R)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative Fc gamma R-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon Fc gamma R engagement and review the available experimental evidence supporting the role of Fc gamma Rs in antiviral protection and pathogenesis through ADE. We explore Fc gamma R engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.
Zhang Q, Bastard P, Liu ZY, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye JQ, Bolze A, Bigio B, Yang R, Arias AA, Zhou QH, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N, Schneider WM, Razooky BS, Hoffmann HH, Michailidis E, Moens L, Han JE, Lorenzo L, Bizien L, Meade P, Neehus AL, Ugurbil AC, Corneau A, Kerner G, Zhang P, Rapaport F, Seeleuthner Y, Manry J, Masson C, Schmitt Y, Schluter A, Le Voyer T, Khan T, Li J, Fellay J, Roussel L, Shahrooei M, Alosaimi MF, Mansouri D, Al-Saud H, Al-Mulla F, Almourfi F, Al-Muhsen SZ, Alsohime F, Al Turki S, Hasanato R, van de Beek DV, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Oler AJ, Tompkins MF, Alba C, Vandernoot I, Goffard JC, Smits G, Migeotte I, Haerynck F, Soler-Palacin P, Martin-Nalda A, Colobran R, Morange PE, Keles S, Colkesen F, Ozcelik T, Yasar KK, Senoglu S, Karabela SN, Rodriguez-Gallego C, Novelli G, Hraiech S, Tandjaoui-Lambiotte Y, Duval X, Laouenan C, Snow AL, Dalgard CL, Milner JD, Vinh DC, Mogensen TH, Marr N, Spaan AN, Boisson B, Boisson-Dupuis S, Bustamante J, Puel A, Ciancanelli MJ, Meyts I, Maniatis T, Soumelis V, Amara A, Nussenzweig M, Garcia-Sastre A, Krammer F, Pujol A, Duffy D, Lifton RP, Zhang SY, Gorochov G, Beziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL
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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

SCIENCE 2020 OCT 23; 370(6515):422-eabd4570
Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3-and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
Wang ZJ, Zhong P, Ma KJ, Seo JS, Yang FW, Hu ZH, Zhang F, Lin L, Wang J, Liu T, Matas E, Greengard P, Yan Z
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Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 inShank3-deficient mice

MOLECULAR PSYCHIATRY 2020 OCT; 25(10):2517-2533
Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of theShank3gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) ofShank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits inShank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors inShank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC ofShank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.
Yang Z, Takai KK, Lovejoy CA, de Lange T
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Break-induced replication promotes fragile telomere formation

GENES & DEVELOPMENT 2020 OCT 1; 34(19-20):1392-1405
TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres-structures that resemble common fragile sites (CFSs)-but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did not generate fragile telomeres. Collectively, these findings indicate that fragile telomeres can arise from BIR-mediated repair of telomeric DSBs.
Kujirai T, Zierhut C, Takizawa Y, Kim R, Negishi L, Uruma N, Hirai S, Funabiki H, Kurumizaka H
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Structural basis for the inhibition of cGAS by nucleosomes

SCIENCE 2020 OCT 23; 370(6515):455-458
The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy, and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo-electron microscopy structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA. In this configuration, all three known cGAS DNA binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA.
Morin PA, Alexander A, Blaxter M, Caballero S, Fedrigo O, Fontaine MC, Foote AD, Kuraku S, Maloney B, McCarthy ML, McGowen MR, Mountcastle J, Nery MF, Olsen MT, Rosel PE, Jarvis ED
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Building genomic infrastructure: Sequencing platinum-standard reference-quality genomes of all cetacean species

MARINE MAMMAL SCIENCE 2020 OCT; 36(4):1356-1366
In 2001 it was announced that the 3.1 billion base (gigabase, Gb) human genome had been sequenced, but after 13 years of work and US$2.7 billion in cost, it was still considered to be only a draft. The initial assembly was missing over 30% of the genome and was made up of over 100,000 sequence fragments (scaffolds) with an average size of just 81,500 base pairs (bp) (International Human Genome Sequencing Consortium, 2004; Stein, 2004). As technologies improved, the draft human genome assembly has been repeatedly refined and corrected. By the time the genome assembly was published in 2004, the average length of scaffolds had increased to over 38 million bp (megabases, Mb) with only a few hundred gaps in the chromosome‐length scaffolds. However, the duplicated and highly repetitive regions of the human genome remained unresolved due to limitations of short‐read sequencing technology that requires piecing the genome together from billions of shorter sequences. Over the last decade, as highly parallel, much less expensive, short‐ and long‐read sequencing technologies have revolutionized genomic sequencing, thousands of individual human genomes have been sequenced, further refining the human genome assembly and characterizing its diversity. Together these genome sequences have produced a “reference‐quality” human genome assembly that covers 95% of the genome with far fewer and smaller gaps compared to the initial version. Despite this vast improvement, the human genome continues to be updated and refined (v. 39, RefSeq accession GCF_000001405.39).
Gleicher N, Darmon S, Molinari E, Zhang L, Hu JJ, Albertini DF, Barad DH
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A form of secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism as new infertility diagnosis

ENDOCRINE 2020 OCT 2; ?(?):?
Background Mediated via the androgen receptor on granulosa cells, models of small growing follicle stages demonstrate dependence on testosterone. Androgen deficiency reduces ovarian response to follicle stimulation hormone (FSH), granulosa cell mass and estradiol (E2) production falls and FSH, therefore, rises. Though potentially of adrenal and/or ovarian origin, androgen deficiency in association with female infertility is almost universally primarily of adrenal origin, raising the possibility that women with presumptive diagnosis of primary ovarian insufficiency (POI), also called primary ovarian failure (POF) may actually suffer from secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism that leads to follicular arrest at small-growing follicle stages. Methods This retrospective cohort study was performed in a private, academically affiliated infertility center in New York City. We searched the center's anonymized electronic research data bank for consecutive patients who presented with a diagnosis of POI, defined by age <41 year, FSH > 40.0 mIU/mL, amenorrhea for at least 6 month, and low testosterone (T), defined as total T (TT) in the lowest age-specific quartile of normal range. This study did not include patients with oophoritis. Since dehydroepiandrosterone sulfate (DHEAS) is the only androgen almost exclusively produce by adrenals, adrenal hypoandrogenism was defined by DHEAS < 100ug/dL. Thirteen of 78 presumed POI women (16.67%) qualified and represented the original study population. POI patients are usually treated with third-party egg donation; 6/13, however, rejected egg donation for personal or religious reasons and insisted on undergoing at least one last IVF cycle attempt (final study population). In preparation, they were supplemented with DHEA 25 mg TID and CoQ10 333 mg TID for at least 6 weeks prior to ovarian stimulation for IVF with FSH and human menopausal gonadotropins (hMG). Since POI patients are expected to be resistant to ovarian stimulation, primary outcome for the study was ovarian response, while secondary outcome was pregnancy/delivery. Results Though POI/POF patients usually are completely unresponsive to ovarian stimulation, to our surprise, 5/6 (83.3%) patients demonstrated an objective follicle response. In addition, 2/6 (33.3%) conceived spontaneously between IVF cycles, while on DHEA and CoQ10 supplementation and delivered healthy offspring. One of those is currently in treatment for a second child. Conclusions This preliminary report suggests that a surprising portion of young women below age 41, tagged with a diagnosis of POI/POF, due to adrenal hypoandrogenism actually suffer from a form of SOI, at least in some cases amenable to treatment by androgen supplementation. Since true POI/POF usually requires third-party egg donation, correct differentiation between POI and SOI in such women appears of great importance and may warrant a trial stimulation after androgen pre-supplementation for at least 6 weeks.
Strujo E, Sanders M, Fiscella K, Thomas M, Johnson B, Deets A, Lucas CS, Holder T, Johal N, Luque A, Cassells A, Williams S, Tobin JN
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COVID-19 impact on multi-site recruitment and enrollment

CLINICAL TRIALS 2020 OCT; 17(5):501-504 Article 1740774520946270